This is a competitive renewal to complete our ongoing study of disseminated tuberculosis (dTB) in HIV infection. Tuberculosis is the most common cause of death from HIV infection in the developing world and dTB represents a substantial proportion of these deaths. Our hypotheses are (1) that most cases of dTB occur in advanced AIDS and represent reactivation or re-infection in persons with waning cellular immunity to mycobacteria, and (2) that if BCG-primed subjects are boosted with an inactivated mycobacterial vaccine in earlyiHIV infection, their subsequent risk of both dTB and pulmonary tuberculosis (pTB) will be reduced by 50%. Heat-inactivated M. vaccae (MV) is a vaccine that protects against tuberculosis in an animal model, is safe and immunogenic in subjects with HIV infection and CD4 counts>200, and boosts mycobacterial immune responses primed by BCG. Our specific aims are: (1) To define risk factors for HIV-associated dTB and to assess the relative contributions of primary infection, re-infection, and reactivation in its pathogenesis, and (2) To assess the safety and efficacy of a prime-boost immunization strategy for the prevention of HIV- associated dTB and pTB. Patient enrollment was delayed one year by the regulatory review process (initial monthly enrollment limits were reduced from 100 to 33) and the need to identify a new study site. We established laboratories and clinical facilities in Dar es Salaam, Tanzania, trained study personnel and developed referral relationships with 22 HIV testing centers. In 3 years we have screened 3228 subjects, enrolled 1303 (57%) of the targeted 2274 BCG-positive subjects, and administered 4695 doses of vaccine. GCP study standards have been met, and multiple reviews by the DSMB based on pre-approved safety criteria have all been satisfactory. We have documented the highest reported rate of previously undiagnosed active tuberculosis in ambulatory patients with HIV (15%), identified a new syndrome of subclinical tuberculosis and shown that 85% of subjects have detectable baseline immune responses to mycobacteria and are primed for booster immunization. A three year renewal is requested to complete enrollment and follow-up. Vaccine efficacy against dTB and pTB will be determined, and in vitro immunologic responses will be used to identify surrogate markers of efficacy. This study has important implications for the reduction of mortality from HIV-associated tuberculosis and for design of new vaccine trials against tuberculosis.